This invention is directed to certain 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide purines, purine nucleosides and purine nucleotides including 3-deaza, 7-deaza and 8-aza derivatives thereof, to their preparation and to using these compounds to treat malignant tumors in vivo.
Certain antimetabolites are known useful cancer chemotherapeutic agents. One such antimetabolite chemotherapeutic agent is 6-mercaptopurine. 6-Mercaptopurine was initially found to be highly active against adenocarcinoma and currently 6-mercaptopurine is utilized as a drug of choice in the treatment of leukemia. Its use in the treatment of leukemia led to dramatic increases in controlling this disease. Other useful antimetabolites are 6-thioguanine and 5-bromouracil. Nucleoside and nucleotide analogs of these and other purines and pyrimidines had been synthesized and tested as antitumor agents.
Purine and pyrimidine nucleosides and nucleotides are ubiquitous throughout biological systems. It further appears that most of the analogs of purines and pyrimidines exert their biological activity only after conversion to a corresponding nucleotide. In view of this, a number of purine and pyrimidine nucleosides and nucleotides have been synthesized and screened for their antitumor properties.
To be an effective chemotherapeutic agent a compound must possess a number of desirable properties. First of all, it must, of course, be an active antitumor agent. Coupled with this, it must not exhibit too great a host toxicity or must exhibit reversible toxicity such that the host is capable of surviving the chemotherapeutic treatment regimen. Optimally the chemotherapeutic agent should not induce the development of drug resistant cell lines. The inducement of drug resistant cell line occurs with certain known chemotherapeutic agents, as for instance, 6-mercaptopurine and cytosine arabinoside.
Further, effective chemotherapeutic agents need to transport to the site in the body inflicted with the neoplastic condition. Thus depending upon the type of tumor, this requires that chemotherapeutic agents be capable of reaching tumor containing organs. This includes being able to effectively penetrate the central nervous system by crossing the blood brain barrier. As is evident by the sparsity of clinically effective chemotherapeutic agents, very few compounds possess a sufficient number of these capabilities to be clinically useful.
Many effective chemotherapeutic agents require repeated dosing in order to progressively diminish and kill the neoplastic cell populations affecting the host. During these repeated administrations of the chemotherapeutic agent it is further advantageous for the agent to not develop resistant cell lines. Because of the development of resistant cells by certain drugs presently used in the treatment of many neoplastic disease states, combinations of drugs are usually utilized. Thus, as resistant cells develop to a first drug, treatment with a second or further drug is often made in an attempt to effectively treat the drug resistant neoplastic cells.
We have found that certain 6-sulfenamide, 6-sulfinamide and 6-sulfonamide purines, purine nucleosides and purine nucleotides and related analogs exhibit one or more of the properties discussed above, and further exhibit significant antitumor activity so as to be useful as antitumor agents in vivo.